ENT symptoms in acute COVID-19: a narrative review.

Introduction

Since December 2019, a pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally [1,2]. A wide spectrum of disease severity has been reported ranging from asymptomatic or oligosymptomatic cases to severe and life-threatening forms of interstitial pneumonia, which can develop into acute respiratory distress syndrome and death.

As the new coronavirus is a respiratory virus which spreads primarily through droplets generated when an infected person coughs or sneezes, it is not surprising that a wide range of symptoms caused by SARS-CoV-2 infection are related to the involvement of the upper respiratory tract. Consequentially, ENT symptoms are among the most common in COVID-19. In our original investigation, upper respiratory tract symptoms accounted for 69% of overall symptoms in patients with mild-to-moderate COVID-19 and were comprised of nasal obstruction, rhinorrhoea, sneezing, ear fullness, sore throat, tearing, neck swelling, hoarseness and dizziness [3]. However, following the phenomenon of the race to publish about coronavirus, there has been an uncontrolled release of poor-quality articles showing the most disparate associations between SARS-CoV-2 infection and symptoms of various types including those of the ENT area [4,5].

We have already reported how smell and taste alterations are among the most frequent symptoms at the onset of the disease affecting around two-third of patients with mild-moderate disease [6], as they are among the most persistent symptoms [7,8], and they are predominant in long-COVID syndrome [9,10], as they can be an indication of infection in the context of patients in home isolation [11], since the self-reported alterations of the olfactory function underestimate the real prevalence and persistence that emerges through psychophysical tests [12,13]. As this topic will be the subject of a separate discussion in this special issue, in this review we will limit the description to non-chemosensory ENT symptoms of SARS-CoV-2 infection.

Upper airway-related general symptoms

The correct definition of the ENT symptomatology in COVID-19 is hampered by two main factors. On one hand, many of the clinical studies aimed at describing the clinical features of COVID-19 are focused on the more severe signs and symptoms of involvement of the lower airways, while completely or partially ignoring upper airway involvement. On the other hand, the extreme spread of COVID-19 makes it difficult to demonstrate a causal link between atypical ENT symptoms and SARS-CoV-2 infection and it is reasonable to assume that at least in some cases this link is actually coincidental.

Many studies have consistently described cough and nasal obstruction as the most common non-chemosensory ENT symptoms of COVID-19. Due to the retrospective design of many studies, the prevalence of ENT symptoms such as cough, sore throat, runny nose and nasal obstruction in the different studies is highly variable with rates ranging from 3 to 90% [14].

In a consecutive series of 202 home-isolated patients with PCR-confirmed SARS-CoV-2 infection, using a validated structured questionnaire, we observed the following prevalence of non-chemosensory ENT symptoms: cough 60%, blocked nose 31%, sore throat 31% and sinonasal pain 17% [6].

A recent meta-analysis reported a pooled prevalence of cough and nasal obstruction of 53 and 26%, respectively, followed by sore throat (18%) and rhinorrhoea (13%). While symptoms like fever, cough, fatigue, vomiting/diarrhoea, and dyspnoea were most common among hospitalised patients, nasal obstruction, sore throat and rhinorrhea were conversely most prevalent in patients with mild-to-moderate COVID-19 [15].

Outstandingly, ENT symptoms are among the first to manifest, and thus their prompt identification can dramatically prevent the spread of the infection [6,16]. Furthermore, olfactory loss and nasal obstruction are often dissociated symptoms and, if they coexist, the evolution of one is independent of the other [7].

Oral manifestations of COVID-19

Although the detection of SARS-CoV-2 in saliva reveals the presence of the virus in the oral cavity, the impact of SARS-CoV-2 on oral diseases is still poorly studied [17]. Numerous studies have described different types of lesions affecting the oral cavity in COVID-19 patients. While for many of these a coincidental relationship is rather probable, while for others lesions a direct or indirect link with COVID-19 seems established [18].

Oral cavity findings, including lingual papillitis, glossitis, aphthous stomatitis, xerostomia and mucositis were observed up to 26% of patients with COVID-19 [19]. Aragoneses et al. [18], in a very comprehensive review and meta-analysis, classified oral manifestations in COVID-19 according to the putative aetiology. Aphthous lesions and oral ulcers are among the most consistently observed manifestations for which a direct aetiological role of SARS-CoV-2 is likely [19,20]. These lesions can affect any sub-site of the oral cavity, although the tongue is more frequently involved. A variable prevalence of oral manifestations including oral ulceration, cheilitis and glossitis were observed in the context of multi-organ involvement, i.e. multisystem inflammatory syndrome and Kawasaki-like disease in children with COVID-19 [21-23]. Furthermore, a substantial group of oral lesions are attributable to iatrogenic lesions, such as intubation injuries, drug reactions and opportunistic infections during SARS-CoV-2 infection [24,25].

In addition, periodontal disease may increase during COVID-19 [26] and on the other hand, a poor periodontal state can favour a vicious circle with an increase in the indexes of inflammation, aspiration of bacteria and consequent increased risk of pneumonia. Although it is difficult to state which of the various oral lesions associated with COVID-19 are the most prevalent, it seems that a higher frequency can be found in older, hospitalised patients with severe infection [27]. The hypothesis that the oral manifestations are secondary lesions resulting from the deterioration of systemic health or treatments for COVID-19 is most probably correct. The pharmacological agents against COVID-19 are related to several adverse reactions, including oral lesions [28].

Salivary alterations

Xerostomia was reported by 50% of patients with a median dryness score of 5 (range: 3-8) and for 76.5% patients mentioning that it was their first-time experiencing xerostomia in their lifetime [29]. The hypothesis is that the xerostomia reported in patients with the COVID-19 occurs due to the neuro-invasive and neurotropism potential of SARS-CoV-2 [30]. In fact, angiotensin-converting enzyme 2 (ACE-2), reported to be the main site of entry of SARS-CoV-2 into the cell, was found to be present in the ductal elements of the salivary glands [31]. Overall, studies are still necessary to unveil the precise pathophysiological mechanism by which SARS-CoV-2 causes the reported xerostomia and taste disturbances [32].

Oropharynx

The oropharyngeal tissue is one of the main harbour sites of the infection, main site of taking the sample for testing and a main source of transmission of infection. However, it was reported that pharyngeal erythema and tonsil enlargement are not common manifestations of SARS-CoV-2 infection, and these signs are present in only about 5 and 1% of cases, respectively [33]. However, sore throat is referred by around one-third of patients [6].

Temporomandibular disorders

Indirectly caused by the coronavirus due to the stress related to the pandemic situation and the governmental choices of the various countries in its management, reports have noted an increased number of people experiencing teeth grinding and oral pain during the COVID-19 pandemic as a consequence of increased stress. On the other hand, stress, anxiety and depression due to COVID-19 lead to increased orofacial pain, TMD and bruxism [34].

Audio-vestibular symptoms

Adult human inner ear tissue has been shown to co-express the angiotensin-converting enzyme 2 receptor for SARS-CoV-2 virus, and the transmembrane protease serine 2 and FURIN cofactors required for virus entry [35]. However, data about possible audio-vestibular dysfunction secondary to SARS-CoV-2 infection are mainly based on case reports and small case series [36,37].

While generic dizziness was self-reported by 14% of patients with mild-to-moderate COVID-19 [6], more specific audio-vestibular symptoms, i.e. sensorineural hearing loss and vertigo, were indeed anecdotally described with authors theorising a direct correlation to SARS-CoV-2 infection mainly based on a temporal association [38].

A more recent study compared evolution of incidence of sudden sensorineural hearing loss and Meniere’s disease from 2016 to 2020 and observed a decrease in the incidence of Meniere’s disease, while the incidence of sudden sensorineural hearing loss remained unchanged from 2016 to 2020 indicating that audio-vestibular symptoms in COVID-19 patients are probably coincidental rather than causal [39]. However, one should consider that the restrictive measures implemented during the pandemic could have reduced exposure to triggers of audio-vestibular diseases and counterbalanced any increase related to SARS-CoV-2 infection.

Thus, based on the current literature, no definitive conclusions can be drawn about the possible clinical impact of SARS-CoV-2 on the inner ear and large case-control studies are necessary to clarify the effect of SARS-CoV-2 infection in the onset of audio-vestibular symptoms.

Regarding hearing disorders, it seems that SARS-CoV-2 infection may cause a worsening of symptoms in patients already suffering from tinnitus. This highlights the diverse response that both internal and external factors have on tinnitus levels. Some authors stated that clinical services should be mindful that tinnitus may be caused by contracting COVID-19 and pre-existing tinnitus may be exacerbated [40]. However, little evidence has been found regarding the onset of new tinnitus contextual to SARS-CoV-2 infection [41] and it is not clear if this could be a direct viral effect or the consequence of ototoxicity of drugs used during hospitalization of patients [42].

COVID-19 and acute otitis media

Concerning a hypothetical link between SARS-CoV-2 infection and otitis media, the literature includes small case series and case reports [43,44]. Although researchers have found the presence of virus in the middle ear of subjects who died from COVID-19, a direct role of SARS-CoV-2 in the aetiopathogenesis of otitis media has not been demonstrated [45].

It is reasonable to hypothesise that a viral infection of the upper airways such as that caused by SARS-CoV-2, in conjunction with Eustachian tube dysfunction, may be complicated with acute or effusive otitis media, similar to what is observed in rhinitis or nasopharyngitis caused by common respiratory viruses [46]. Thus, the concomitant occurrence of otitis media and COVID-19 should be considered a complication rather than a manifestation of COVID-19.

COVID-19 and facial palsy

Different clinical series on the prevalence of Bell’s palsy (BP) in the pandemic are emerging in the literature. Even if some authors sustained a direct correlation between sars-CoV-2 infection and Bell’s palsy in the first phase of the pandemic [47,48], the most recent epidemiological data have reduced the causal relationship [49] and there seems to be no association other than mere chance.

Complications of nasal swab

In addition to the more common symptoms treated above, it should be mentioned that indirectly the need to perform frequent nasal swabs for health surveillance during COVID pandemic implies a, albeit minimal, rate of complications, like nasal bleeding, foreign body retention (broken swab) [50,51] and cases of cerebrospinal fluid leak [52,53].

Conclusions

Consistent with the fact that SARS-CoV-2 is a respiratory virus, many symptoms observed during the acute phase reflect active upper airway infection. Importantly, upper airway symptoms, i.e. dry cough or coughing up mucus, blocked nose, rhinorrhoea, sinonasal pain and sore throat as well as chemosensory alterations are among the first to manifest, and thus their prompt identification can dramatically prevent the spread of infection (Tab. I). However, for other ENT symptoms, i.e. such as oral lesions, audio-vestibular changes and facial palsy, a causal relation has not been demonstrated (Tab. I). Due to the extensive spread of COVID-19, it is realistic to assume that in some cases the link between SARS-CoV-2 infection and atypical ENT symptoms can be coincidental. Furthermore, there has been an uncontrolled release of poor-quality articles showing the most disparate associations mainly based on a temporal association between SARS-CoV-2 infection and symptoms of various types including those of the ENT area. Finally, the evaluation of the incidence trends in ENT diseases during the COVID-19 pandemic in order to generate hypotheses on the direct role of SARS-CoV-2 in some ENT diseases is complicated by the fact that the restrictive measures implemented during the pandemic may have modulated the onset of ENT symptoms in the opposite direction.

Table I.

Definitive, probable, possible and complication-related ENT symptoms of COVID-19.

Definitive symptoms	Probable symptoms	Possible symptoms	COVID-19 complication-related symptoms
Cough [6,14,15,16]	Aphthous stomatitis [18,19,20]	Sudden hearing loss [36,37,38]	Intubation injuries [24]
Sore throat [6,14,15,16]	Cheilitis [21,22,23]	Vertigo [36,37]	Periodontal disease [26]
Nasal obstruction [6,7,14,15,16]	Glossitis [21,22,23]	Facial palsy [47,48,49]	Drug reactions [28]
Rhinorrhea [6,14,15,16]	Xerostomia [29,30,31]		Bruxism [34]
Hyposmia/Anosmia [6,7,8,9,10,11,12,13]	Dizzness [6]		Temporomandibular disorders [34]
Hypogeusia [6,7,8,9,10,11,12,13]	Tonsillitis [33]		Nasal swab complications [50,51,52,53]
Sinonasal pain [6,10]			Otitis media [43,44,45]

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Both authors played a substantial role in conception, literature searching, drafting and revision of the manuscript.

Ethical consideration

Ethics approval was not required for this study because it was based on published studies.